This invention relates to 2- and 6-substituted-1-carbadethiapen-2-em-3-carboxylic acids (I) and the pharmaceutically acceptable salt, ester and amide derivatives thereof which are useful as antibiotics: ##STR2## wherein R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: ##STR3## wherein, relative to the above listed substituents on R.sup.6, R.sup.7, and R.sup.8, the groups R.sup.1 and R.sup.2 are independently selected from: R.sup.6, R.sup.7 and R.sup.8 and include inter alia: hydrogen, --OR.sup.1 and --SR.sup.1 (wherein R.sup.1 is broadly defined here; for example, alkoxy and alkylthiol having 1-6 carbon atoms), --NR.sup.1 R.sup.2 (R.sup.1 and R.sup.2 are defined here), alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and phenyl substituted by alkyl, OH, NR.sup.1 R.sup.2, and the aliphatic portion has 1-6 carbon atoms; heteroalkyl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms.
Further, relative to the 2-substituent --SR.sup.8 of I and in particular to R.sup.8 radicals which carry an amino group (--NH.sub.2) or an N-substituted amino group (--NR.sup.1 H), and which can be represented conveniently as: --R.sup.8 --NH.sub.2, and --R.sup.8 --NR.sup.1 H, respectively, there exists the following groups classed under previously defined R.sup.8 : ##STR4## wherein: R.sup.8, R.sup.1 and R.sup.2 are as defined above; the methylene carbon atom, which is joined to R.sup.8 via nitrogen, may be a member of a ring formed on joinder of its substituents. With regard to the above-defined groups A-F, it will be appreciated that, while they represent distinct entities, subsequent reference to "amidino" and "guanidino" embodiments of I will be intended to speak generically of all such forms--including all canonical tautomeric forms. Also embraced, but not depicted above for clarity, are all remaining N-quaternized forms which nevertheless are fairly suggested by structures A-F. It will also be appreciated that such amidino and quanidino embodiments of I are capable of zwitterionic behavior. This feature to the extent that it is helpful in appreciating the nature of such embodiments of I, is discussed below.
A particularly preferred subclass of such "amidine" and "guanidine" values for R.sup.8 may be represented by ##STR5## wherein: n=2, 3, 4, 5, or 6; m=0 or 1; X and Y are selected from R.sup.1 and --NR.sup.1 R.sup.2 ; the methylene carbon may become a member of a ring caused by the joinder of its substituents X and Y; wherein R.sup.1 and R.sup.2 are as defined above.
Further relative to R.sup.8 there exists the following groups classed under previously defined R.sup.8 : ##STR6## such groups give rise to embodiments of I which will be referred to herein as "carbamimidoyls"; R.sup.8, R.sup.1 and R.sup.2 are as defined above. A particularly preferred subclass of such carbamimidoyls may be represented by: ##STR7## wherein: n=0, 1, 2, 3, 4, 5 or 6; and R.sup.1 and R.sup.2 are as previously defined; the two nitrogen atoms demonstrated in the above structure, may be joined, via their substituents, to form a ring which is indicated by the dotted lines.
Specific examples of representative and preferred values for R.sup.6, R.sup.7 and R.sup.8 in the definition of antibiotics I are given below.
It should be noted that the final products of this invention (I) wherein R.sup.8 contains a basic functionally such as amino, amidino, guanidino, or carbamimidoyl can exist in either neutral or zwitterionic (internal salt) forms. In the zwitterionic form, the basic function is protonated and positively charged and the carboxyl group is deprotonated and negatively charged. The zwitterionic (or internal salt) form is the predominant species under most conditions and is in equilibrium with a minor amount of the uncharged, neutral species. The equilibrium process is conveniently visualized as an internal acid-base neutralization. The neutral and zwitterionic forms are shown below. ##STR8## wherein B is a basic group such as NH.sub.2, NHR.sup.1, NR.sup.1 R.sup.2, amidino, guanidino, carbamimidoyl, and B.sup..sym. H is a protonated basic group such as N.sup..sym. H.sub.3, N.sup..sym.H.sub.2 R.sup.1, ##STR9## Further, the final products of this invention I wherein R.sup.8 contains a positively charged, quaternary nitrogen function such as ammonium, amidinium, guanidinium, or carbamimidinium can exist as zwitterionic (internal salt) forms or as external salt forms. The preferred form of this product group is the zwitterionic or internal salt form. These forms are shown below: ##STR10## wherein Q.sup..sym. is a quarterized nitrogen group such as --N.sym.(R.sup.1).sub.3 ##STR11## and HX is an acid; wherein X is a pharmaceutically acceptable anion such as those listed in U.S. Pat. No. 4,194,047, issued 3/18/80 which is incorporated herein by reference.
This invention also relates to the carboxyl derivatives of I which are antibiotics and which may be represented by the following generic structure (I): ##STR12## wherein X' is oxygen, sulphur or NR' (R'=H or lower alkyl having 1-6 carbon atoms); and R.sup.3' is, inter alia, representatively selected from the group consisting of hydrogen, conventional blocking groups such as trialkylsilyl, acyl and the pharmaceutically acceptable salt, ester and amide moieties known in bicyclic .beta.-lactam antibiotic art; the definition of R.sup.3' is given in greater detail below.
This invention also relates to process for the preparation of such compounds (I); pharmaceutical compositions comprising such compounds; and to methods of treatment comprising administering such compounds and compositions when an antibiotic effect is indicated.
There is a continuing need for new antibiotics. For unfortunately, there is no static effectiveness of any given antibiotic because continued wide scale usage selectively gives rise to resistant strains of pathogens. In addition, the known antibiotics suffer from the disadvantage of being effective only against certain types of microorganisms. Accordingly, the search for new antibiotics continues.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inaminate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram negative bacteria such as E. coli, Pseudomonas, Proteus morganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated.